PREVALENCE OF SUBCLINICAL AND UNDIAGNOSED OVERT HYPOTHYROIDISMIN HABITUAL ABORTION

andundiagnosed overt hypothyroidism was found in 24 cases (12%) of women. Sixteen women (8%) had subclinical hypothyroidism,eight (4%) had undiagnosed overt hypothyroidism. Results were compared to women with ongoing pregnancies. Results: The prevalence of subclinical and undiagnosed overt hypothyroidism in the pregnancy loss population was 12% (24 /200), where 8 %( 16/200) were subclinical, and 4% (8/200) were undiagnosed overt. In the control population, prevalence of hypothyroidism was 1.5% (3/200).

The antibodies that appear most frequently are: First group of antibodies: Antithyroid Peroxidase Antibody or TPO Ab (Ab is short for antibody) this is also known as Antithyroid Microsomal Ab.
Second group of antibodies: Antithyroglobulin Antibody or TG Ab.
Third group of antibodies: Thyroid Stimulating Immunoglobulin or TSI Ab.
The first group, the TPO Ab, are found raised in Hashimoto's disease -otherwise known as autoimmune thyroiditis.
Here the cells of the thyroid gland are attacked and slowly destroyed. Patients with these antibodies present either have Hashimoto's, or are going to have it with subsequent reduction of thyroid function. (Elevated levels are found in virtually all cases of Hashimoto's disease and they will also be raised in 65% of patients with Graves' disease).
The next group is the TG Ab. These levels rise as well as the TPO Ab levels in autoimmune thyroiditis, but to a lesser degree.(2-7) The third group, the TSI Abs, exert their effect by targeting the TSH (thyroid stimulating hormone) receptors in the thyroid gland, and activate them abnormally, thus stimulating the thyroid gland to overproduce thyroid hormones. This of course is Graves' disease and these Thyroid Stimulating Immunoglobulins are the chief cause of it. (7-8) Both the thyroid stimulating immunoglobulin antibodies and the antithyroid peroxidase antibodies may be present in an autoimmune (Hashimoto's) thyroiditis and in Graves' disease in some degree at least.
Thyroid autoantibodies are found in 5-15% of women of childbearing age, and chronic autoimmune thyroiditis is the main cause of hypothyroidism during pregnancy. (3) The alteration in thyroid hormone regulation in pregnancy due to the increase in plasma volume expansion, the increasein thyroid binding globulin (TBG) caused by human chorionic gonadotrophin (HCG), and the relative iodine deficiency inpregnancy, results in a 10-15% lower free T4 level compared to non-pregnant women (9).
The benefits of universal screening for thyroid dysfunction (primarily hypothyroidism) are not justified by currentevidence. Undertake a high-risk screening for thyroid disease by measurement of TSH in women with: History of hyperthyroid or hypothyroid disease, PPT, or thyroid lobectomy.
Symptoms or clinical signs suggestive of thyroid under-function or over-function including anaemia, elevatedcholesterol, and hyponatraemia.
Family history of thyroid disease.
Other autoimmune disorders.
Previous therapeutic head or neck irradiation. Goitre.

Type 1 diabetes.
History of recurrent miscarriage or PTD. (10) Other causes of thyroid insufficiencytreatment of hyperthyroidism (radioiodineablation or surgery) or surgery for thyroid tumours.
The demands of thyroid hormone,however, increase due to the initial increase in TBG, the thyrotropic action of HCG, which causes an increase in TBGand free T4 and alterations in thyroid metabolism, particularly at placental level at later gestationadapt to these changes result in subclinical or even overt hypothyroidism in normally euthyroid women.
Thyroid hormone is an important contributory factor to normal fetal brain development.
At early gestational stages the presence of thyroid hormones in fetal structures can only be explained by transfer of maternal thyroid hormones to the fetal compartmentbecause fetal production of thyroid hormones does not become efficient until mid-gestation.
Prior to 12 weeks' gestation, maternal thyroxine (but not fT3) crosses the placenta. From 12 weeks onwards, fetal thyroid function is controlled independently of themother, provided that her iodine intake is adequate.
The fetal thyroid begins concentrating iodine at 10-12 weeks and is under control of fetal pituitary TSH by approximately 20 weeks. (14) TSH does not cross the placenta. However, clinically significant amounts of maternal T4 do cross the placenta. In addition, TSH-releasing hormone (TRH), iodine, TSHreceptor (TSH-R) antibodies, and antithyroid drugs (ATDs) cross the placenta readily.
The incidence of pregnancy loss is 15-20%. Recurrent miscarriage, defined as at least three consecutive miscarriages,occurs in 1% of women (24).
Stillbirth occurs in 1 in 200 pregnancies. Both overt and subclinical hypothyroidisms are associated with stillbirth. Three proposed hypotheses for the association of thyroid autoimmunity and pregnancy lossare; firstly, it may reflect a generalized activation of the maternal immune system, secondly it delays conception,therefore increasing the risk of miscarriage due to older maternal age and thirdly, it may reflect a subtle deficiencyin thyroid hormone (14, 15, 16).
In overt hypothyroidism, treatment with levothyroxine is known to alleviate maternal symptoms and improve pregnancyoutcome (8).
In subclinical hypothyroidism, the evidence for treatment is lacking. However, The Endocrine Society ClinicalPractice Guidelines concluded that there is benefit to treatment, with low incidence of adverse outcomes, and thereforeadvocated levothyroxine treatment in subclinical hypothyroidism (1).
Levothyroxine requirements in patients with overthypothyroidism increase from early first trimester and the dosage of levothyroxine may need to be increased 30-50% by4-6 weeks gestation. A target level of TSH less than 2.5µU/mL is recommended (17, 18).

Methods:-
We conducted a prospective analysis of thyroid function tests (TFT) in women attending the high risk pregnancy unit of Benha university hospital obstetrics and gynecology departmentbetween January 2015 and January 2017 attended by women with a history of recurrentmiscarriage, late miscarriage, or perinatal death.
Women havethe indicated medical investigations done at the time of pregnancy loss to ensure availability of the results duringconsultation. Investigations include a thrombophilia screen, thyroid function, autoimmune screening, and parentalkaryotyping.

Inclusion criteria
Women with recurrent miscarriage, mid-trimester miscarriage andstillbirth were included. Recurrent miscarriage was defined as three or more consecutive first trimester miscarriages, mid-trimester miscarriage was defined as miscarriage between 14 to 24 weeks, and stillbirth was defined as intrauterine fetal death after 24 weeks

Exclusion criteria
Those with sporadic or non-recurrent miscarriage were excluded. Women withknown thyroid and autoimmune disorders were excluded. Women found to have other causative factors were also excluded.

Laboratory evaluation
Thyroid function tests (TFT) were performed at the time of diagnosis of pregnancy loss. Cases with overt or subclinical hypothyroidism haverepeated at their follow-up high risk pregnancy unit (HRPU) visit.
Reference ranges for free T4and TSH in the first, second and third trimester used were 12.05-19.60pmol/L and 0.33  Median free T4 and TSH in the first, second, and third trimesters were 14.40pmol/L and 1.16mU/L,12.90pmol/L and 1.16mU/L, and 11.40pmol/L and 1.59mU/L respectively. Free T4 levels in the late miscarriage group and the stillbirth group were significantly lower than those in therecurrent miscarriage group (p-value 0.001 and 0.03 respectively), likely due to the later gestation of thesepregnancies. Free T4 levels between the late miscarriage group and the stillbirth group did not differ significantly.
TSH levels did not differ significantly between all three groups.
In the control population, 1.5% (3/200) weresubclinical, and overt ypothyroidism The prevalence of subclinical and undiagnosed overt hypothyroidism in thepregnancy loss group was significantly higher than the control group (p-value 0.0032).

Discussion:-
In the current study, the prevalence of subclinical and undiagnosed overt hypothyroidism in the pregnancy loss cohort was 12%,of which 8% were subclinical and 4% overt hypothyroidism. In the general pregnant population, the prevalence of overt and subclinicalhypothyroidism is reported as 1.5%. These findings support theassociation of overt and subclinical hypothyroidism with pregnancy loss. (1) A previous study demonstrated that inuntreated hypothyroid women, 60% of the overtly hypothyroid women and 71% of the subclinically hypothyroid women hadmiscarriage (2).
Several reasons may account for the changes of thyroid function in pregnant women: (1) relative iodine deficiency during pregnancy; (2) the effects of human chorionic gonadotropin (hCG) on the activation of thyroid function stimulates the secretion of thyroid hormones, which could inhibit adenohypophysis function and suppress the levels of thyrotropin; (3) elevated levels of oestrogen during pregnancy, increasing serum thyroid binding globulin (TBG) and raising the concentrations of serum total thyroxine; and (4) the effect of the placenta on thyroxinedeiodination (25) In adequately treated women, the risk was minimal. In current study, 12% of women with habitual abortion were hypothyroid.
Another reportshowed that 3.8% of women with first trimester miscarriages had subclinical hypothyroidism.Study included women with sporadic miscarriage(6).
Most recently, an increased incidence ofpregnancy loss in women with TSH between 2.5-5.0 mIU/L in the first trimester was demonstrated, calling for redefiningthe upper limits of TSH in the first trimester of pregnancy(4).
Our study showed that 12% of women with pregnancy losshad TSH levels above 2.5mIU/L, supporting the evidence that increased TSH alone can be associated with pregnancy loss.
Recently, Maraka, etal.reported that pregnancy with SCH (subclinical hypothyroidism) is closely associated with a higher foetal mortality (miscarriage rate and stillbirth rate) in a systematic analysis (22) Universal screening has never been clinically justified due tothe lack of evidence supporting treatment of subclinical hypothyroidism, and the lack of quality studies demonstratingits cost-effectiveness (19, 20).
Targeted screening of women at risk is advocated instead (19, 21).However, this canpotentially miss 30% of those with thyroid disorders. Universal screening can detect twice as many women with thyroiddisorders in early pregnancy compared to targeted screening, but whether treatment should then be initiated for allis unclear (21-23).
Meta-analysis of pregnant women before 20 weeks done by Yibing Zhang in 2017 revealed increase in the rate of habitual abortion when cases proved to have subclinical hypothyroidism (25) Compared to OH (overt hypothyroidism), the incidence of complications related to SCH (subclinical hypothyroidism) is lower. However, the prevalence of adverse outcomes, including spontaneous miscarriage, placental abruption, preterm birth, fetal distress and preeclampsia, has increased in recent studies [3].
In conclusion, this study has demonstrated a significant prevalence of undiagnosed overt and subclinical hypothyroidismin women with pregnancy loss, supporting the association between pregnancy loss and hypothyroidism.